Neurotrophins are known to contribute to critical developmental processes in the nervous system. Recent studies by the applicant have shown that neurotrophins are expressed in the developing mammalian olfactory epithelium during the time that synaptic connections are being made with the developing forebrain. At this time, cells in the rostral telencephalon express the appropriate tyrosine kinase trk receptors for these neurotrophins and the olfactory bulbs begin to form. The spatial and temporal patterns of expression suggest the hypothesis that developing sensory neurons in the olfactory epithelium anterogradely transport specific neurotrophin factors to responsive forebrain neurons and thereby contribute to development of the olfactory bulb. The goals of the proposed research are to test aspects of this hypothesis. The first specific aim is to identify the specific cell types expressing different neurotrophins and their receptors in the epithelium and bulb. In particular we wish to determine if neurotrophin mRNAs are expressed by olfactory sensory neurons and if neurotrophin proteins are localized within olfactory nerve projections. Cell types will be identified by colocalization of neurotrophin/receptor mRNA and protein with phenotypic markers specific for subpopulations of olfactory cells The second aim is to determine if the olfactory nerve anterogradely transports neurotrophins from the epithelium to the bulb, and if this has functional consequences. Studies will determine if colchicine treatment increases neurotrophin immunoreactivity in sensory neurons while decreasing immunoreactivity in olfactory axons and terminals. We will also evaluate the redistribution of radiolabeled neurotrophins applied to the olfactory epithelium, and measure levels of bulb trk phosphorylation following such treatment. The third aim is to determine if early neurotrophic factor deprivation leads to morphological or phenotypic abnormalities in the bulb. This will be accomplished by evaluating olfactory system development in mice carrying targeted mutations in neurotrophin genes. The levels, distribution and cellular localization of neurotrophin and trk expression, and of phenotypic cell markers, will be examined in the normal and neurotrophin-deprived olfactory system. Differences in patterns of cell death in forebrain and bulb neuron morphology will also be examined. The final aim is to determine if early neurotrophin deprivation has functional consequences in this system by evaluating bulb trk phosphorylation and odor-stimulated c-fos expression in knockout mice and control littermates. Results of these studies will contribute to our understanding of the molecular signals that regulate mammalian forebrain development.